1. Field of the Invention
This invention relates to certain polyamines found to be present in the venom of the Agelenopsis aperta spider. The polyamines and the pharmaceutically-acceptable salts thereof are antagonists of excitatory amino acid neurotransmitters which neurotransmitters affect cells including neuronal cells of a variety of organisms including invertebrates and vertebrates. This invention also relates to the use of such polyamines and their salts in antagonizing excitatory amino acid neurotransmitters which neurotransmitters affect cells such as cells in the nervous system of an organism, per se, in the treatment of excitatory amino acid neurotransmitter mediated diseases and conditions in a mammal and control of invertebrate pests, and to compositions comprising said polyamines and salts thereof.
2. Background of the Invention
It has been reported that the venom of the spider Agelenopsis aperta contains at least two toxins which affect calcium currents Jackson, H., et al., Soc. Neu. Sci. Abstr. 12:1078 (1987). Those authors disclose a toxin, referred to therein as AG2, which has a molecular weight of less than 1,000 daltons and appears to suppress calcium currents in a broad range of tissues Further, Jackson, H., et al., Soc. Neu. Sci. Abstr. 12:730 (1986) report another toxin from Agelenopsis aperta comprising a component of about 6,000 M.W. That toxin is reported to effect presynaptic blockade of transmission and it has been suggested that the toxin blocks calcium channels associated with the release of neurotransmitter.
Certain polyamines found to be present in the venom of the Agelenopsis aperta spider are disclosed in U.S. patent application Ser. No. 07/346,181, filed Apr. 28, 1989 and assigned to the assignees hereof. Those polyamines and the pharmaceutically-acceptable salts thereof are disclosed therein as blockers of excitatory amino acid receptors in cells and one such polyamine, B.sub.1 therein, is also disclosed as a blocker of calcium channels in cells. Those polyamines are described therein as follows: ##STR1##
AGEL 504:
a compound having the following identifying characteristics:
(a) present in a fraction from crude venom of the Agelenopsis aperta spider which elutes off a C-18 Vydac.RTM. 22 mm.times.250 mm, 300 .ANG. pore size, 10 .mu. particle size column using a flow rate of 15 ml/min. and a solvent system using a linear gradient program of 5% .fwdarw. 20% B, 95% .fwdarw. 80% A [0 .fwdarw. 30 min.] then 20% .fwdarw. 70% B, 80% .fwdarw. 30% A [30 .fwdarw. 55 min.], where A is 0.1% aqueous TFA and B is acetonitrile, at about 22.75 minutes;
(b) present in a fraction of the fraction described in (a), above, which elutes off a C-18 Vydac.RTM. 22 mm.times.250 pore size, 300 .ANG. pore size, 10 .mu. particle size column using a flow rate of 15 ml/min. and a solvent system using a non-linear gradient program of 0% .fwdarw. 0% B, 100% .fwdarw. 100% A [0 .fwdarw. 5 min.], then 0% .fwdarw. 10% B, 100% .fwdarw. 90% A [5 .fwdarw. 20 min.] (Waters curve 1) then 10% .fwdarw. 20% B, 90% .fwdarw. 80% A [20 .fwdarw. 30 min.] (Waters curve 6) then 20% .fwdarw. 50% B, 80% .fwdarw. 50% A [30 .fwdarw. 40 min.](Waters curve 11), where A is 0.1% aqueous TFA and B is acetonitrile, at about 21.5 minutes; and
(c) FAB MS: high resolution 505.3861 calculated for C.sub.27 H.sub.48 N.sub.6 O.sub.3.
Compounds which are excitatory amino acid neurotransmitter antagonists have a variety of utilities. Excitatory amino acid neurotransmitter antagonists can find clinical application in the treatment of such conditions as stroke, cerebral ischemia, neuronal degeneration disorders such as Alzheimer's disease and epilepsy and as psychotherapeutants, among others. See Excitatory Amino Acids in Health and Disease, D. Lodge, Ed., John Wiley and Sons Ltd., New York, N.Y. 1988, the teachings of which are incorporated herein by reference. Further, such compounds are useful in the study of the physiology of cells such as neuronal cells and in the control of invertebrate pests.